Activation of cell-free mtDNA-TLR9 signaling mediates chronic stress-induced social behavior deficits.
Activation of cell-free mtDNA-TLR9 signaling mediates chronic stress-induced social behavior deficits.
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DOI：
10.1038/s41380-023-02189-7
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发表时间：
2023-09
影响因子：
11
通讯作者：
Pillai, Anilkumar
中科院分区：
文献类型：
--
作者：
Tripathi, Ashutosh;Bartosh, Alona;Whitehead, Carl;Pillai, Anilkumar
炎症和社会行为缺陷与许多神经精神障碍有关。慢性压力是抑郁症和其他精神健康状况的主要风险因素，已知会增加炎症反应和社会行为障碍。线粒体功能障碍在慢性应激条件下已被发现，然而，将线粒体功能障碍与应激诱导的社会行为缺陷联系起来的机制尚不清楚。在这项研究中，我们发现慢性束缚应激(RS)可导致小鼠血清中无细胞线粒体DNA(cf-mtDNA)水平显著升高，系统脱氧核糖核酸酶I(DNase I)治疗可减轻RS所致的社会行为缺陷。我们的发现揭示了线粒体吞噬和线粒体抗病毒信号蛋白(MAVS)在介导慢性应激诱导的cf-mtDNA水平和社会行为变化中的潜在作用。此外，我们还发现抑制Toll样受体9(TLR9)可以减轻线粒体DNA诱导的社会行为缺陷。总之，这些发现表明，cf-mtDNA-TLR9信号在调节应激诱导的社会行为缺陷方面起着关键作用。
Inflammation and social behavior deficits are associated with a number of neuropsychiatric disorders. Chronic stress, a major risk factor for depression and other mental health conditions is known to increase inflammatory responses and social behavior impairments. Disturbances in mitochondria function have been found in chronic stress conditions, however the mechanisms that link mitochondrial dysfunction to stress-induced social behavior deficits are not well understood. In this study, we found that chronic restraint stress (RS) induces significant increases in serum cell-free mitochondrial DNA (cf-mtDNA) levels in mice, and systemic Deoxyribonuclease I (DNase I) treatment attenuated RS-induced social behavioral deficits. Our findings revealed potential roles of mitophagy and Mitochondrial antiviral-signaling protein (MAVS) in mediating chronic stress-induced changes in cf-mtDNA levels and social behavior. Furthermore, we showed that inhibition of Toll-like receptor 9 (TLR9) attenuates mtDNA-induced social behavior deficits. Together, these findings show that cf-mtDNA-TLR9 signaling is critical in mediating stress-induced social behavior deficits.
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发表时间：
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